Preclinical studies suggest that the mesolimbic dopamine (DA) system to the nucleus accumbens is critically involved in cocaine addiction. Yet alterations of DA transmission in the ventral striatum of cocaine abusers are still poorly understood. Recent progress in positron emission tomograph (PET) camera resolution permits direct evaluation of the mesolimbic DA function in human cocaine users. In preliminary data, we probed the responsivity of DA neurons to an amphetamine challenge, by measuring the decrease in [11C]raclopride binding potential resulting from the increase in synaptic DA induced by amphetamine. In healthy subjects, amphetamine-induced DA release is higher in ventral compared to dorsal striatum. In contrast, studies in detoxified subjects with a long history (15 years) of heavy cocaine dependence revealed a dramatic blunting of amphetamine-induced DA release in the ventral striatum. This finding suggests that years of cocaine abuse might be associated with a severe pathology of mesolimbic DA neurons. The general aim of this proposal is to confirm this observation in a larger group of subjects (specific aim 1), and to combine this measurement with determination of dopamine transporters (DAT) availability with the selective DAT PET radiotracer [11C]PE21 (specific aim 2). As the DAT is exclusively located on DA terminals, this evaluation will provide a comprehensive picture of presynaptic DA function in the ventral striatum in cocine abusers. Alteration in presynaptic DA function might be associated with development of tolerance to cocaine. This hypothesis will be investigated by correlating the imaging results with the subjective effects of cocaine self administration (specific aim 3). If confirmed, such a result would support the general hypothesis that years of cocaine exposure result in pathological adaptation of mesolimbic DA function. Given the role of this system in incentive learning, it is predicted that such a pathology would result in inability to learn and encode new "natural" rewarding behaviors and would contribute to the maintenance of the addictive behavior. Understanding the neurochemical abnormalities associated with the development and maintenance of cocaine addiction is critical to guide future treatment interventions.